This is a five year grant proposal from an highly trained early NHLBI investigator in an outstanding biomedical research environment with world-renowned local and international collaborators focused on the contributions of the enzyme/cytokine macrophage migration inhibitor factor (MIF) in cigarette smoke (CS)-induced emphysematous tissue remodeling. Our research has focused on positive and negative molecular regulators of CS-induced alveolar damage/apoptosis as possible modifiers of emphysematous phenotype in chronic obstructive pulmonary disease (COPD). CS is the most common environmental cause of COPD/emphysema in the developed world and is responsible for 85-90 percent of COPD/emphysema mortality. This disease leads to greater than 100,000 deaths annually, placing it among the top 5 causes of pre-mature death in this country. No current therapies target alveolar destruction, the histopathologic hallmark of emphysema. Further, there is a clinical need to define new, safe, biomarkers that correlate with risk of disease development, severity, and progression to better prognosticate and direct therapy. We have been able to show that MIF regulates alveolar cell apoptosis in vitro and that it is modified in ad animal model of emphysema both transcriptionally and post-transnationally. Mice genetically deficient in MIF are hypersensitive to smoke-induced emphysema with more oxidative damage, defective antioxidant defenses, and failure to activate the master anti-oxidant transcription factor NRF2. Further, we demonstrate significantly decreased serum MIF in patients with severe COPD (GOLD classification IV). The three overlapping and integrated specific aims proposed here are directed at understanding the role and mechanism(s) by which 1) CS exposure alters the enzymatic function of MIF and its impact on tissue injury; 2) MIF potentiates NRF2-dependent anti-oxidant gene expression, and 3) chronic CS exposure alters MIF expression and its relationship with emphysematous phenotype in humans.